CN104926806B - Method for synthesizing lamivudine intermediate - Google Patents
Method for synthesizing lamivudine intermediate Download PDFInfo
- Publication number
- CN104926806B CN104926806B CN201410109115.4A CN201410109115A CN104926806B CN 104926806 B CN104926806 B CN 104926806B CN 201410109115 A CN201410109115 A CN 201410109115A CN 104926806 B CN104926806 B CN 104926806B
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- compound shown
- compound
- meso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 title claims abstract description 24
- 229960001627 lamivudine Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000007530 organic bases Chemical class 0.000 claims abstract description 9
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- -1 bicyclic carboxylic ester Chemical class 0.000 claims abstract description 4
- 238000006206 glycosylation reaction Methods 0.000 claims abstract description 4
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940104302 cytosine Drugs 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 238000006266 etherification reaction Methods 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims abstract description 3
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 21
- 238000005406 washing Methods 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 239000000543 intermediate Substances 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 abstract description 2
- 229910000077 silane Inorganic materials 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CHFYSOCPHBZWAG-UHFFFAOYSA-N 1,3-oxathiolan-2-ylmethanol Chemical compound OCC1OCCS1 CHFYSOCPHBZWAG-UHFFFAOYSA-N 0.000 description 1
- PJXVQPWEQYWHRL-UHFFFAOYSA-N 1-acetyl-4-aminopyrimidin-2-one Chemical compound CC(=O)N1C=CC(N)=NC1=O PJXVQPWEQYWHRL-UHFFFAOYSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing a lamivudine intermediate, which comprises the following steps: carrying out a methyl etherification reaction on the compound shown in the formula VI and a hydrochloric acid methanol solution to obtain a compound shown in a formula V; carrying out reduction reaction on the compound shown in the formula V and sodium borohydride in ethanol to obtain a compound shown in a formula IV; carrying out esterification reaction on a compound shown as a formula IV and chlorocarbonate under the action of organic base to generate bicyclic carboxylic ester so as to obtain a compound shown as a formula III; carrying out acylation reaction on the compound shown in the formula III and acetic anhydride under the catalysis of acid to obtain a compound shown in a formula II; carrying out glycosylation reaction on the compound shown in the formula II and silane protected N4-acetamido cytosine under the catalysis of trimethyl iodosilane to obtain a meso compound shown in the formula I'; and (3) recrystallizing and resolving the meso compound shown in the formula I' to obtain the lamivudine intermediate shown in the formula I. The method has the advantages of simple operation, low cost, high product purity and the like.
Description
Technical Field
The invention relates to a method for synthesizing a lamivudine intermediate, belonging to the technical field of drug synthesis.
Background
Lamivudine is a nucleoside reverse transcriptase inhibitor, is a deoxycytidine nucleoside analogue, inhibits the replication of Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV), is called Lamividine in English, has a chemical name of (2R-cis) -4-amino-1- (2-hydroxymethyl-1, 3-oxathiolane hybrid cyclopent-5-yl) -1H-pyrimidine-2-ketone, and has a structural formula as follows:
lamivudine was first developed by BioChemPharma, Canada, and was used to treat AIDS (WO 91/17159) and hepatitis B (EP 0474119), especially hepatitis B. Lamivudine has two chiral centers and exists in 4 stereoisomers, wherein the isomer with 2R, 5S (2R-cis) -configuration has the strongest activity against HIV and HBV and has lower cytotoxicity to some cells than enantiomers or racemates thereof.
For the acquisition of optically active lamivudine, several routes have been reported in the literature, among which the chinese patent CN101307048 filed by the present applicant discloses one of the following synthetic routes:
through industrial production, the process is found to have the problems that the process is not suitable for industrial scale-up production, and mainly has the problems that emulsification is easy to generate in the post-treatment washing process, a large amount of degradation impurities are easy to generate in the concentration process, enantiomers are difficult to separate, and the like.
Disclosure of Invention
In order to solve the above problems in the prior art, the present invention aims to provide a method for synthesizing lamivudine intermediate, so as to better satisfy the requirements of industrial production of lamivudine.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing lamivudine intermediates, comprising the following reaction scheme:
the method is characterized in that:
the reaction a is to perform a methyl etherification reaction on the compound shown in the formula VI and a hydrochloric acid methanol solution, and after the reaction is finished, the compound is neutralized by inorganic base and then is subjected to reduced pressure concentration to obtain a compound shown in a formula V;
the reaction b is to perform reduction reaction on the compound shown in the formula V and sodium borohydride in ethanol to obtain a compound shown in a formula IV;
the reaction c is to carry out esterification reaction on the compound shown in the formula IV and chlorocarbonic ester under the action of organic base to generate bicyclic carboxylic ester, so as to obtain a compound shown in a formula III (commonly known as chlorobicyclic carboxylic ester);
performing acylation reaction on the compound shown in the formula III and acetic anhydride at the temperature of 8-10 ℃ under the catalysis of acid, washing the compound with water and a saturated sodium bicarbonate aqueous solution in sequence until the reaction is finished, washing the compound with a saturated sodium chloride aqueous solution until the reaction is neutral, drying the compound, concentrating the solution under reduced pressure, and regulating the pH value of the concentrated solution to be 7 by using an organic base in the concentration process to obtain the compound shown in the formula II;
the reaction e is to carry out glycosylation reaction on the compound shown in the formula II and silane-protected N4-acetamido cytosine at 0-5 ℃ under the catalysis of trimethyl iodosilane; after the reaction is finished, firstly, washing excessive iodine by using a sodium thiosulfate aqueous solution, then adjusting the pH value of an organic phase to be neutral by using alkali, then, carrying out reduced pressure concentration, dissolving the concentrated residue by using ethyl acetate or n-hexane, then, washing by using an alkali solution, drying by using anhydrous sodium sulfate, and finally, carrying out reduced pressure concentration until no liquid flows out to obtain a meso-compound shown in the formula I';
and the reaction f is to perform recrystallization resolution on the meso compound shown in I': firstly, adding a meso compound shown in a formula I' into an alcohol solvent, and heating until reflux and clearance; dripping an alkane solvent under a reflux state; after dripping, stirring and crystallizing at the temperature controlled below 5 ℃; filtering, washing, drying and vacuum drying to obtain the lamivudine intermediate shown in the formula I.
Preferably, the inorganic base in the reaction a is a mixture of sodium carbonate and potassium carbonate.
Preferably, the organic base in reaction c is pyridine.
Preferably, the acid in the reaction d is sulfuric acid, the organic solvent is ethyl acetate, n-hexane, n-heptane or n-pentane (preferably ethyl acetate and n-hexane), and the organic base is selected from pyridine, triethylamine, dimethylamine, diethylamine, diisopropylethylamine or triethylenediamine (preferably triethylamine).
The alcohol solvent in the reaction f includes but is not limited to methanol, ethanol, isopropanol and n-butanol, and ethanol, isopropanol or n-butanol are preferred.
The mass amount of the alcohol solvent in the reaction f can be 1-10 times, preferably 3-6 times of that of the meso compound shown in the formula I'.
The alkane solvent in the reaction f includes but is not limited to n-hexane, n-heptane, cyclohexane and n-pentane, and n-hexane or n-heptane is preferred.
The mass amount of the alkane solvent in the reaction f can be 5-15 times, preferably 6-10 times that of the meso compound shown in the formula I'.
Compared with the prior art, the invention has the following remarkable beneficial effects:
1) and sodium borohydride is used as a reducing agent in the reaction b, so that the method has the advantages of high conversion rate, short reaction time, recovery and reutilization of the obtained byproduct menthol through crystallization, not only saves the raw material cost, but also ensures that the compound shown in the formula IV can meet the purity requirement only through extraction and washing.
2) The reaction d adopts acetic anhydride for acetylation reaction, and has the advantages of high reaction speed, high conversion rate, simple and convenient post-treatment and the like; and in the post-treatment concentration process, the pH value of the concentrated solution is regulated and controlled to be maintained at 7 by adopting organic base, so that the degradation of the compound shown as the formula II can be effectively inhibited, and the obtained compound shown as the formula II has the advantages of high purity, high yield and the like.
3) The reaction e adopts trimethyl iodosilane to catalyze the glycosylation reaction, and has the advantages of good stereoselectivity, high reaction conversion rate and the like; especially, when in post-treatment, the concentrated residue is dissolved by ethyl acetate or normal hexane, so that the emulsification phenomenon of dichloromethane in the prior art can be effectively avoided, the post-treatment operation is simple, the loss of materials is avoided, and the cost is saved.
4) The reaction f adopts the mixing treatment of the alcohol solvent and the alkane solvent, so that the fluidity of the crystallized materials is well solved, the problems that the crystallized solid which adopts a single alcohol solvent as a resolution solvent is in a gel-like agglomerate state, almost has no fluidity, and the industrial operation such as material transfer filtration can not be realized are solved, the resolution efficiency is greatly improved, and the lamivudine intermediate I with the diastereoisomer less than 1 percent can be obtained by only one-time resolution.
In a word, the method for synthesizing the lamivudine intermediate can effectively solve the problems of easy emulsification, easy generation of a large amount of degradation impurities in the concentration process, difficult enantiomer separation and the like in the prior art, has the advantages of simple operation, low cost, high product purity and the like, and can better meet the requirements of industrial production of lamivudine.
Detailed Description
The present invention will be described more fully hereinafter with reference to the following examples.
Example 1
Adding 1kg of a compound shown as a formula VI into 1vol% of hydrochloric acid methanol solution, and reacting for 2-2.5 hours at 20-25 ℃; after the reaction is finished, adding 0.05kg of potassium carbonate into a reaction bottle, and then adjusting the pH value to 7-8 by using sodium carbonate; and (4) carrying out suction filtration, and concentrating at 40-45 ℃ to obtain a compound (oily substance) shown in the formula V for later use.
1.2kg of 95vol% ethanol and 0.2kg of sodium borohydride were added to a 5L reaction flask; dissolving the oily compound shown in the formula V in 0.8kg of 95vol% ethanol, and dropwise adding the dissolved oily compound into a sodium borohydride ethanol solution at the temperature of 20-25 ℃, wherein the dropwise adding speed is controlled to be completed within 4.5-5 hours; after dripping, heating to 38-42 ℃, keeping the temperature, stirring and reacting for about 2 hours, and monitoring by TLC to finish the reaction; after the reaction is finished, adjusting the pH value to 6-6.5 by using 15wt% of hydrochloric acid aqueous solution; then extracting with dichloromethane, collecting the organic phase, adding 0.25kg of anhydrous sodium sulfate and 0.05kg of anhydrous magnesium sulfate, drying, filtering, and concentrating under reduced pressure to obtain the compound shown in formula IV for later use.
Adding 1.13kg of dichloromethane into the compound shown in the formula IV, stirring and dissolving, adding 0.34kg of pyridine at 5-10 ℃, and then dropwise adding 0.565kg of menthol formyl chloride; after the dropwise addition, heating to 20-25 ℃, keeping the temperature for reacting for about 2-2.5 hours, and monitoring by TLC to finish the reaction; and (3) finishing the reaction, washing the organic phase by using a 5wt% hydrochloric acid aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence, then drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound shown in the formula III for later use.
Under the protection of nitrogen, adding 0.75kg of the compound shown in the formula III, 10.7kg of ethyl acetate and 1.08kg of acetic anhydride into a 20L reaction bottle, uniformly stirring, cooling to 8-10 ℃ in an ice bath, and then dropwise adding a sulfuric acid (0.104 kg) -ethyl acetate (2 kg) solution for 1.5-2 hours; after dripping, controlling the temperature to be 8-10 ℃ and continuing to carry out heat preservation reaction for about 2-2.5 hours until the reaction is complete; after the reaction is finished, 3kg of water is sequentially adopted for washing twice, the saturated sodium bicarbonate aqueous solution is washed to be neutral, the saturated sodium chloride aqueous solution is washed, the drying and the decompression concentration are carried out, and the pH value of the concentrated solution is regulated and controlled to be 7.0 by triethylamine in the concentration process; concentrating and drying to obtain the compound shown in the formula II, and directly putting the compound into the next reaction.
Adding 3.2kg of dichloromethane to dissolve the compound shown in the formula II obtained in the previous step, then cooling to 25-35 ℃, adding acetylcytosine protected by silane dissolved in dichloromethane, cooling to-5 ℃, dropwise adding 0.4745kg of iodotrimethylsilane, controlling the temperature to be 0-5 ℃ after dropwise adding, keeping the temperature for reaction, and reacting completely for about 24 hours; after the reaction is finished, 4.167kg of 10wt% sodium thiosulfate solution is added into the reaction bottle, and the mixture is stirred and washed; separating out an oil phase, adjusting the pH value to 7-7.5 by using about 0.136kg of triethylamine, controlling the temperature to be 40-45 ℃, and concentrating under reduced pressure until no liquid drops drop; and then adding 3.5kg of ethyl acetate into the concentrated reaction bottle, stirring until the reaction solution is clear, washing with 3.5kg of 7wt% sodium bicarbonate aqueous solution and 3.5kg of saturated sodium chloride aqueous solution in sequence, drying with anhydrous sodium sulfate, and concentrating under reduced pressure until no liquid flows out to obtain the meso-compound shown in the formula I'.
Example 2
Taking 50g of the meso-compound shown in the formula I', adding 300g of ethanol, heating to reflux and dissolve, slowly dropping 500g of n-hexane under a reflux state, cooling to 0-5 ℃, keeping the temperature and stirring for 1 hour, filtering, washing, collecting a filter cake, and vacuum-drying for 5 hours at 50 ℃ to obtain 21.2g of solid, namely the lamivudine intermediate shown in the formula I, wherein the mass yield is 42.4%, the HPLC purity is 98.5%, and the content of the diastereoisomer is 0.86%.
Example 3
Taking 50g of the meso-compound shown in the formula I', adding 200g of n-butanol, heating to reflux and clear under stirring, then slowly dropping 450g of n-hexane under a reflux state, cooling to 0-5 ℃, keeping the temperature and stirring for 1 hour, filtering, washing, collecting a filter cake, and vacuum drying for 5 hours at 50 ℃ to obtain 24.3g of solid, namely the lamivudine intermediate shown in the formula I, wherein the mass yield is 48.6%, the HPLC purity is 98.9%, and the content of the diastereoisomer is 0.35%.
Example 4
Taking 50g of the meso-compound shown in the formula I', adding 200g of ethanol, heating to reflux and dissolve the meso-compound under stirring, then slowly dropping 400g of n-heptane under a reflux state, cooling to 0-5 ℃, keeping the temperature and stirring for 1 hour, filtering, washing, collecting a filter cake, and drying under vacuum at 50 ℃ for 5 hours to obtain 22.5g of solid, namely the lamivudine intermediate shown in the formula I, wherein the mass yield is 45%, the HPLC purity is 99.1%, and the content of diastereoisomers is 0.2%.
Example 5
Taking 50g of the meso-compound shown in the formula I', adding 150g of isopropanol, heating to reflux and dissolve the meso-compound under stirring, then slowly dropping 400g of n-hexane under a reflux state, cooling to 0-5 ℃, keeping the temperature and stirring for 1 hour, filtering, washing, collecting a filter cake, and drying in vacuum at 50 ℃ for 5 hours to obtain 25.1g of solid, namely the lamivudine intermediate shown in the formula I, wherein the mass yield is 50.2%, the HPLC purity is 98.9%, and the content of the diastereoisomer is 0.35%.
Example 6
Taking 50g of the meso-compound shown in the formula I', adding 150g of isopropanol, heating to reflux and dissolve the meso-compound under stirring, then slowly dripping 300g of cyclohexane under a reflux state, cooling to 0-5 ℃, keeping the temperature and stirring for 1 hour, filtering, washing, collecting a filter cake, and drying under vacuum at 50 ℃ for 5 hours to obtain 22g of solid, namely the lamivudine intermediate shown in the formula I, wherein the mass yield is 44%, the HPLC purity is 98.5%, and the content of diastereoisomers is 0.69%.
Example 7
Taking 50g of the meso-compound shown in the formula I', adding 150g of isopropanol, heating to reflux and dissolve the meso-compound under stirring, then slowly dropping 400g of n-heptane under a reflux state, cooling to 0-5 ℃, keeping the temperature and stirring for 1 hour, filtering, washing, collecting a filter cake, and drying under vacuum at 50 ℃ for 5 hours to obtain 24.8g of solid, namely the lamivudine intermediate shown in the formula I, wherein the mass yield is 49.6%, the HPLC purity is 99.2%, and the content of the diastereoisomer is 0.15%.
Finally, it must be said here that: the above embodiments are only used for further detailed description of the technical solutions of the present invention, and should not be understood as limiting the scope of the present invention, and the insubstantial modifications and adaptations made by those skilled in the art according to the above descriptions of the present invention are within the scope of the present invention.
Claims (4)
1. A method for synthesizing lamivudine intermediates, comprising the following reaction scheme:
the method is characterized in that:
the reaction a is to perform a methyl etherification reaction on the compound shown in the formula VI and a hydrochloric acid methanol solution, and after the reaction is finished, the compound is neutralized by inorganic base and then is subjected to reduced pressure concentration to obtain a compound shown in a formula V;
the reaction b is to perform reduction reaction on the compound shown in the formula V and sodium borohydride in ethanol to obtain a compound shown in a formula IV;
the reaction c is to carry out esterification reaction on the compound shown in the formula IV and chlorocarbonate under the action of organic alkali to generate bicyclic carboxylic ester, so as to obtain a compound shown in a formula III;
performing acylation reaction on the compound shown in the formula III and acetic anhydride at the temperature of 8-10 ℃ under the catalysis of acid, washing the compound with water and a saturated sodium bicarbonate aqueous solution in sequence until the reaction is finished, washing the compound with a saturated sodium chloride aqueous solution until the reaction is neutral, drying the compound, concentrating the solution under reduced pressure, and regulating the pH value of the concentrated solution to be 7 by using an organic base in the concentration process to obtain the compound shown in the formula II;
reaction e is the reaction of a compound of formula II with silane-protected N catalyzed by iodotrimethylsilane4Performing glycosylation reaction on the-acetamido cytosine at 0-5 ℃; after the reaction is finished, firstly, washing excessive iodine by using a sodium thiosulfate aqueous solution, then adjusting the pH value of an organic phase to be neutral by using alkali, then, carrying out reduced pressure concentration, dissolving the concentrated residue by using ethyl acetate or n-hexane, then, washing by using an alkali solution, drying by using anhydrous sodium sulfate, and finally, carrying out reduced pressure concentration until no liquid flows out to obtain a meso-compound shown in the formula I';
and the reaction f is to perform recrystallization resolution on the meso compound shown in I': firstly, adding a meso compound shown in a formula I 'into isopropanol, wherein the mass consumption of the isopropanol is 3 times of that of the meso compound shown in the formula I', and heating until refluxing and clearing; dropwise adding n-heptane in a reflux state, wherein the mass consumption of the n-heptane is 8 times that of the meso compound shown in the formula I'; after dripping, cooling to 0-5 ℃, and stirring for 1 hour under heat preservation; filtering, washing and vacuum drying to obtain the lamivudine intermediate shown in the formula I.
2. The method of claim 1, wherein: the inorganic base in the reaction a is a mixture of sodium carbonate and potassium carbonate.
3. The method of claim 1, wherein: the organic base in reaction c is pyridine.
4. The method of claim 1, wherein: in the reaction d, the acid is sulfuric acid, the organic solvent for the acylation reaction is ethyl acetate, n-hexane, n-heptane or n-pentane, and the organic base is selected from pyridine, triethylamine, dimethylamine, diethylamine, diisopropylethylamine or triethylene diamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410109115.4A CN104926806B (en) | 2014-03-22 | 2014-03-22 | Method for synthesizing lamivudine intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410109115.4A CN104926806B (en) | 2014-03-22 | 2014-03-22 | Method for synthesizing lamivudine intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104926806A CN104926806A (en) | 2015-09-23 |
| CN104926806B true CN104926806B (en) | 2020-03-24 |
Family
ID=54114257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410109115.4A Active CN104926806B (en) | 2014-03-22 | 2014-03-22 | Method for synthesizing lamivudine intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104926806B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116199679A (en) * | 2022-12-23 | 2023-06-02 | 吉斯凯(苏州)制药有限公司 | Industrial preparation method of lamivudine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321641A (en) * | 2001-04-02 | 2001-11-14 | 中国科学院长春应用化学研究所 | Preparation method of lamifudin |
| CN1618795A (en) * | 2003-11-18 | 2005-05-25 | 博瑞生物医药技术(苏州)有限公司 | Process of preparing slereo iosmer of 1,3-oxapantane kind nucleotide |
| CN101307048A (en) * | 2007-05-18 | 2008-11-19 | 上海迪赛诺医药发展有限公司 | Method for preparing lamivadin by stereoselectivity |
-
2014
- 2014-03-22 CN CN201410109115.4A patent/CN104926806B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321641A (en) * | 2001-04-02 | 2001-11-14 | 中国科学院长春应用化学研究所 | Preparation method of lamifudin |
| CN1618795A (en) * | 2003-11-18 | 2005-05-25 | 博瑞生物医药技术(苏州)有限公司 | Process of preparing slereo iosmer of 1,3-oxapantane kind nucleotide |
| CN101307048A (en) * | 2007-05-18 | 2008-11-19 | 上海迪赛诺医药发展有限公司 | Method for preparing lamivadin by stereoselectivity |
Non-Patent Citations (1)
| Title |
|---|
| Practical enantioselective synthesis of lamivudine (3TCTM) via a dynamic kinetic resolution;Michael D. Goodyear，等;《Tetrahedron Letters》;20051019;第46卷;第8535页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104926806A (en) | 2015-09-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7296882B2 (en) | Compositions and methods for phosphoramidite and oligonucleotide synthesis | |
| CN105330609B (en) | A kind of method for preparing LCZ696 | |
| CN113956312B (en) | Preparation method of mopilavir | |
| EP2802562B1 (en) | Process for the preparation of travoprost | |
| CN101591371B (en) | Method for preparing gemcitabine or analogues thereof through halogen-exchange fluorination | |
| CN107311875A (en) | The synthetic method of aramine | |
| CN113024396B (en) | Preparation method of oseltamivir and intermediate thereof | |
| CN111892636A (en) | Synthesis method of azvudine | |
| CN109867684B (en) | Preparation method of II-type clopidogrel hydrogen sulfate | |
| CN104926806B (en) | Method for synthesizing lamivudine intermediate | |
| CN109232700B (en) | Efficient synthesis method of altrenogest | |
| CN106986766B (en) | Preparation method of tafluprost | |
| CN111559995B (en) | Preparation process of ascorbic acid ethyl ether | |
| CN101759698B (en) | Method for preparing entecavir | |
| CN111943937A (en) | Synthesis method of triphenyl candesartan | |
| CN106928149B (en) | Preparation method of olaparib | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| CN101514163B (en) | Optically pure Sibutramine and process for preparing salt derivative thereof | |
| CN113004245B (en) | Preparation method of desloratadine | |
| CN102558268A (en) | Process for preparing tauroursodeoxycholic acid hydrate | |
| CN107586288A (en) | A kind of purification process of Vonoprazan fumarate | |
| CN112457353A (en) | Synthesis method of beta-nicotinamide riboside chloride | |
| JP3902384B2 (en) | Method for purifying optically active α-methyl-bis-3,5- (trifluoromethyl) benzylamines | |
| JP2012513970A (en) | Method for recovering beta-acetylfuranoside | |
| CN103524360A (en) | Method for synthesizing ivabradine key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240401 Address after: No.1 Chenli Road, coastal industrial park, Binhai Economic Development Zone, Yancheng City, Jiangsu Province Patentee after: JIANGSU PUXIN PHARMACEUTICAL Co.,Ltd. Country or region after: China Address before: No. 9125 Hunan Highway, Huinan Town, Pudong New Area, Shanghai, 201300 Patentee before: SHANGHAI ACEBRIGHT PHARMACEUTICALS Co.,Ltd. Country or region before: China |